Because the fundamental defect in both acute myocardial infarction (MI) and ischemic cardiomyopathy is myocyte loss, stem cell therapy to regenerate lost myocardium is conceptually appealing. Multiple clinical trials have been performed in patients with acute MI and chronic ischemic heart failure using a variety of cell types, including bone marrow stem cells, mesenchymal stem cells (MSCs), and cardiac resident stem cells.1 However, the results from clinical and preclinical studies have been variable, with generally modest benefits in human trials, and disappointingly low levels of cell persistence, engraftment, and cardiomyocyte differentiation. Emerging evidence suggests that rather than the generation of new cardiac tissue, the cardioprotective effects observed with cell therapy may be in large part secondary to secreted paracrine factors that enhance endogenous reparative pathways.1 These factors may include proteins, RNA, bioactive lipids, and metabolites, and the clustering of these factors into exosomes may facilitate their delivery.

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The low levels of stem cell engraftment observed in these studies suggest that a harsh cardiac microenvironment may compromise cell survival and reparative potential. Importantly, both acute MI and chronic heart failure are characterized by heightened inflammation. Acute MI induces abrupt and massive cardiomyocyte death that triggers intense sterile inflammation to clear necrotic cells, followed by a reparative phase of inflammation resolution, neovascularization, and scar formation.2 Ischemic cardiomyopathy is accompanied by inappropriately sustained chronic inflammation, with expansion of innate3,4 and adaptive5 immune cells and the elaboration of proinflammatory cytokines that promote adverse left ventricular remodeling. Attenuation of the cardiac inflammatory response may, therefore, represent a fruitful approach to enhance the efficacy of cell therapy in these diseases.

In this context, MSCs are particularly attractive as a therapeutic. In addition to being multipotent cells capable of differentiating into a variety of cell types, …